Retinoids have broad effects including development, growth, cell death, and anti-oxidation. Their actions have been extensively studied in the skin, eye, and in many types of cancer. The liver is a major retinoic acid (RA) target site. Surprisingly, the action of RA in the liver has received very little attention. Our data generated in the past 10 years have uncovered many novel roles of retinoids in the liver. We showed that in the liver retinoids and their receptors have a broad spectrum of actions ranging from xenobiotic biotransformation to cholesterol, fatty acid, bile acid, carbohydrate, and amino acid homeostasis. In addition, hepatic retinoid signaling regulates cell proliferation and apoptosis as well as inflammation. Thus, we hypothesize that RA and its receptors regulate liver metabolism and function in general. The objective for the current application is twofold: to provide an unbiased hepatic genome-wide RA receptor target-gene profile in a gender-specific manner and to elucidate the mechanism by which RA and its receptors regulate gene transcription and expression. Among the diverse pathways, we propose to focus on studying the role of RA/receptors in regulating lipid homeostasis because hepatocyte RXR1 (retinoid x receptor 1) deficiency increases and RA treatment reduces serum lipids in vivo. Furthermore, lack of hepatic RXR1 increases the susceptibility to develop steatosis and steatohepatitis. Three specific aims are proposed to study the global effect of RA/receptors in the liver and the underlying mechanisms. Aim 1 determines genome-wide RA/receptor target genes/pathways in the liver in a gender- specific manner using ChIP-sequencing and microarray analysis. The generated data may account for gender differences in liver function and susceptibility to liver disease. Aim 2 studies the mechanism by which retinoid- mediated pathways regulate lipid homeostasis. We propose to study the mechanisms that regulate two clusters of lipid homeostasis genes, which either do or do not respond to RA but both depend on hepatic RXR1 for their expression. The transcriptional machinery, which dictates RA responsiveness, will be elucidated. Aim 3 studies the mechanism by which RA regulates its own signaling. We will test the hypothesis that RA and hepatic RXR1 regulate genes via modification of chromatin structure and epigenetic signatures. The mechanism by which retinoid signaling is controlled at the basal and RA-regulated level in the liver will be addressed at the transcriptional and epigenetic level. The proposed study may be the first attempt to uncover the fundamental effects of retinoid signaling within the liver with an emphasis on lipid homeostasis. The generated data will have a huge impact on cancer, metabolic syndrome, diabetes, and cardiovascular disease as well as toxicology.